title: CD40 gene silencing reduces the progression of experimental lupus nephritis modulating local milieu and systemic mechanisms.
abstract: Lupus nephritis (LN) is an autoimmune disorder in which co-stimulatory signals have been involved. Here we tested a cholesterol-conjugated-anti-CD40-siRNA in dendritic cells (DC) in vitro and in a model of LPS to check its potency and tissue distribution. Then, we report the effects of Chol-siRNA in an experimental model of mice with established lupus nephritis. Our in vitro studies in DC show a 100% intracellular delivery of Chol-siRNA, with a significant reduction in CD40 after LPS stimuli. In vivo in ICR mice, the CD40-mRNA suppressive effects of our Chol-siRNA on renal tissue were remarkably sustained over a 5 days after a single preliminary dose of Chol-siRNA. The intra-peritoneal administration of Chol-siRNA to NZB/WF1 mice resulted in a reduction of anti-DNA antibody titers, and histopathological renal scores as compared to untreated animals. The higher dose of Chol-siRNA prevented the progression of proteinuria as effectively as cyclophosphamide, whereas the lower dose was as effective as CTLA4. Chol-siRNA markedly reduced insterstitial CD3+ and plasma cell infiltrates as well as glomerular deposits of IgG and C3. Circulating soluble CD40 and activated splenic lymphocyte subsets were also strikingly reduced by Chol-siRNA. Our data show the potency of our compound for the therapeutic use of anti-CD40-siRNA in human LN and other autoimmune disorders.
authors.affiliation: Laboratory of Experimental Nephrology, IDIBELL.Hospital Universitari de Bellvitge, L'Hospitalet, Barcelona, Spain.
authors.forename: Èlia
authors.initials: È
authors.lastname: Ripoll
authors.forename: Ana
authors.initials: A
authors.lastname: Merino
authors.forename: Immaculada
authors.initials: I
authors.lastname: Herrero-Fresneda
authors.forename: Josep M
authors.initials: JM
authors.lastname: Aran
authors.forename: Montse
authors.initials: M
authors.lastname: Goma
authors.forename: Nuria
authors.initials: N
authors.lastname: Bolaños
authors.forename: Laura
authors.initials: L
authors.lastname: de Ramon
authors.forename: Oriol
authors.initials: O
authors.lastname: Bestard
authors.forename: Josep M
authors.initials: JM
authors.lastname: Cruzado
authors.forename: Josep M
authors.initials: JM
authors.lastname: Grinyó
authors.forename: Juan
authors.initials: J
authors.lastname: Torras
mesh_terms: D000419:Albuminuria / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D019013:CD40 Antigens / Q000235:genetics* / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D003176:Complement C3 / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D003713:Dendritic Cells / Q000378:metabolism; D018450:Disease Progression; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D007668:Kidney / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008181:Lupus Nephritis / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010950:Plasma Cells / Q000276:immunology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics*; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D014162:Transfection
chemical_list: D000974:Antibodies, Antinuclear; D019013:CD40 Antigens; D003176:Complement C3; D016207:Cytokines; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D034741:RNA, Small Interfering